A multispecific antibody confers pan-reactive SARS-CoV-2 neutralization and prevents immune escape

Misasi, J.; Wei, R. R.; Wang, L.; Pegu, A.; Wei, C.-J.; Oloniniyi, O.; Zhou, T.; Zhao, B.; Choe, M.; Boruszczak, M.; Chen, M.; Leung, K.; Li, J.; Yang, E. S.; Yang, Z.-Y.; Zhang, Y.; Carlton, K.; Harris, D. R.; Ivleva, V. B.; Lei, P.; Liu, C.; Longobardi, L.; Olia, A. S.; Shi, W.; Wolff, J. J.; Gall, J.; Koup, R. A.; Kwong, P. D.; Mascola, J. R.; Nabel, G. J.; Sullivan, N. J.

doi:10.1101/2022.07.29.502029

Home/Archive/bioRxiv

bioRxiv · 10.1101/2022.07.29.502029

A multispecific antibody confers pan-reactive SARS-CoV-2 neutralization and prevents immune escape

View original source ↗Export metadata ↓

Abstract

Summary ParagraphDespite effective countermeasures, SARS-CoV-2 persists worldwide due to its ability to diversify and evade human immunity1. This evasion stems from amino-acid substitutions, particularly in the receptor-binding domain of the spike, that confer resistance to vaccines and antibodies 2-16. To constrain viral escape through resistance mutations, we combined antibody variable regions that recognize different receptor binding domain (RBD) sites17,18 into multispecific antibodies. Here, we describe multispecific antibodies, including a trispecific that prevented virus escape >3000-fold more potently than the most effective clinical antibody or mixtures of the parental antibodies. Despite being generated before the evolution of Omicron, this trispecific antibody potently neutralized all previous variants of concern and major Omicron variants, including the most recent BA.4/BA.5 strains at nanomolar concentrations. Negative stain electron microscopy revealed that synergistic neutralization was achieved by engaging different epitopes in specific orientations that facilitated inter-spike binding. An optimized trispecific antibody also protected Syrian hamsters against Omicron variants BA.1, BA.2 and BA.5, each of which uses different amino acid substitutions to mediate escape from therapeutic antibodies. Such multispecific antibodies decrease the likelihood of SARS-CoV-2 escape, simplify treatment, and maximize coverage, providing a strategy for universal antibody therapies that could help eliminate pandemic spread for this and other pathogens.

Explore related subjects

immunology Preprint

Keep this discovery

Explore connections, maps & timelines

BibTeX RIS

Misasi, J., Wei, R. R., Wang, L., Pegu, A., Wei, C.-J., Oloniniyi, O., Zhou, T., Zhao, B., Choe, M., Boruszczak, M., Chen, M., Leung, K., Li, J., Yang, E. S., Yang, Z.-Y., Zhang, Y., Carlton, K., Harris, D. R., Ivleva, V. B., Lei, P., Liu, C., Longobardi, L., Olia, A. S., Shi, W., Wolff, J. J., Gall, J., Koup, R. A., Kwong, P. D., Mascola, J. R., Nabel, G. J., Sullivan, N. J.. 2022-07-29. A multispecific antibody confers pan-reactive SARS-CoV-2 neutralization and prevents immune escape. https://doi.org/10.1101/2022.07.29.502029

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

Proliferation and mutation as humoral immune response

The affinity maturation process, through which antibodies acquire relatively high affinity for an invading pathogen, involves complex mechanisms whose relative importance is not yet fully understood. This study proposes an analytical model of this process, to investigate the main factors governing proliferation and mutation and assess their respective roles. The model suggests that the immune system should not be expected to follow a single, rigid evolutionary pattern, as a wide range of proliferation and mutation strategies can yield nearly optimal outcomes. Keywords: Antibody, antigen, affinity, B-cell, mutation, proliferation

immunology↗

bioRxiv2026

Proteome-wide discovery of novel diagnostic antigens for coccidioidomycosis

Coccidioidomycosis, commonly called Valley Fever (VF), caused by Coccidioides spp., is an understudied fungal disease that accounts for a substantial fraction of pneumonias in endemic areas. Diagnosis remains challenging because the mainstay of diagnosis is serology, and current assays have modest sensitivity in early infection. Discovery of new antigens could improve serologic detection early in disease. Here, we use PepSeq, a DNA-programmable serology platform, to represent the complete proteome of Coccidioides within a library of 244,000 DNA-barcoded peptides. By profiling antibody reactivity at the protein and epitope levels in VF patients, naturally infected pigtail macaques, and healthy controls, we identify numerous previously-unrecognized antigens and epitopes, including some shared between humans and macaque responses. When translated into a pooled peptide ELISA, we show that a subset of identified antigens can discriminate VF cases from controls in an independent cohort with high accuracy (AUC = 0.91). These findings establish high-dimensional peptide serology as a scalable approach for fungal antigen discovery and identify new targets for improved VF diagnosis.

immunology↗

bioRxiv2026

Establishing an ex vivo platform for molecular profiling of skin structural cells using frozen human skin biopsies

Skin structural cells, including keratinocytes, melanocytes, endothelial cells, and fibroblasts, play critical roles in the development of chronic inflammatory skin disease. Inflammatory stimuli induce transcriptional reprogramming and epigenetic changes in skin structural cells, which contribute to disease pathogenesis. Although two-dimensional (2D) and three-dimensional (3D) skin culture models have been widely used to investigate inflammatory responses in skin structural cells, ex vivo systems that maintain skin structure and cellular composition remain limited. To address this gap, we explored using frozen skin biopsies as an experimental platform to study the responses of skin structural cells to inflammatory stimuli. Using a simple air-liquid interface culture method on permeable Transwell inserts, we showed that viable skin structural cells that retain cell-type-specific transcriptional profiles can be recovered from frozen skin biopsies after prolonged in vitro culture. Stimulation with IFN-{gamma} induced robust transcriptional and chromatin accessibility changes that were largely resolved after stimulus removal, with transcriptional responses to secondary stimulation comparable to the primary stimulation. Treatment of cultured skin biopsies with histone-modifying enzyme inhibitors effectively altered global histone modification levels, but did not substantially affect the transcriptional resolution of IFN-{gamma}-induced responses. Collectively, these findings establish cryopreserved human skin biopsies as a scalable ex vivo platform that enables mechanistic studies of inflammatory responses of multiple populations of skin structural cells.

immunology↗